Illicit drugs such as methamphetamine (METH) alter immune functions and decreases host resistance. There is an association between METH abuse and enhanced susceptibility to infections;however, underlying mechanisms are largely unknown. High incidence of HIV-1 infection in METH abusers and potential effects of METH on immune system underscore clinical significance of METH-HIV-1 co-morbidity. Defective immune responses could lead to the accelerated HIV-1 infection in the peripheral organs and central nervous system (CNS). Preliminary data point to the oxidative stress as one of possible causes of METH induced immune dysfunction. Indeed, our preliminary studies indicate that METH exposure elicits oxidative stress in T cells and upon T-cell receptor stimulation show T cell proliferation and decreases cytokine production. T cells exposed to METH demonstrate modulation of genes controlling in immune cell activation and T cell surface markers. Therefore, we hypothesize that the oxidative stress caused by METH in T lymphocytes dampens immune responses, impairs T cell activation and proliferation leading to enhanced progression of HIV-1 infection. Using a combination of in vitro systems and animal model for HIV-1 encephalitis chronically exposed to METH, we will address the following questions: (1) What are the potential implications of METH- induced oxidative stress on T cell functions? (2) What are the mechanisms underlying impaired T cell immune responses mediated by oxidative stress associated with METH? (3) How does T cell dysfunction affect the adaptive immune system responses to HIV-1 infection in and outside of CNS? Antioxidants and specific signaling inhibitors will be utilized to delineate pathways involved in these effects. We believe that the proposed works are highly significant as they will uncover novel mechanisms mediating combined effects of HIV-1 and METH abuse on immunity and propose therapeutic approaches based on these investigations. PUBLIC HEALTH RELEVANCE Methamphetamine is a highly addictive stimulant abused by millions of Americans and is known to alter immune function and increase susceptibility to infection. Epidemiological studies indicate growing evidence of the association between METH abuse and an increased incidence of HIV-1 infections. However, the apparent causal interrelationship between METH abuse and susceptibility to HIV-1 infection or its progression are largely unknown. This proposal aims to understand putative mechanisms of immune dysfunctions in the setting of METH abuse and HIV-1 infection.